Drug and Alcohol Dependence 131 (2013) 136–142 Contents lists available at SciVerse ScienceDirect Drug and Alcohol Dependence j ourna l ho me p age: www.elsevier.com/locate/drugalcdep The effects of varenicline on stress-induced and cue-induced craving for cigarettes Lara A. Ray a,b,∗ , Katy Lunny a , Spencer Bujarski a , Nathasha Moallem a , Jennifer L. Krull a , Karen Miotto b a University of California, Los Angeles, Department of Psychology, United States b University of California, Los Angeles, Department of Psychiatry and Biobehavioral Sciences, United States a r t i c l e i n f o Article history: Received 5 September 2012 Received in revised form 11 December 2012 Accepted 12 December 2012 Available online 5 January 2013 Keywords: Varenicline Stress Cue-exposure Craving Nicotine dependence Human laboratory a b s t r a c t Background: Varenicline is a partial agonist of the  4  2 nicotinic acetylcholine receptor approved by the FDA for the treatment of nicotine dependence. While the clinical efficacy of varenicline for smok- ing cessation is well-supported, its biobehavioral mechanisms of action remain poorly understood. This randomized, crossover, placebo-controlled, human laboratory study combines guided imagery stress exposure with in vivo presentation of cigarette cues to test the effects of varenicline on stress-induced and cue-induced craving for cigarettes. Method: A total of 40 (13 females) daily smokers (≥10 cigarettes per day) completed a guided imagery exposure (stress and neutral) followed by the presentation of cigarette cues at the target dose of vareni- cline (1 mg twice per day) and on matched placebo. Results: Multilevel regression models revealed a significant main effect of varenicline (p < .01) such that it reduced cigarette craving across the experimental paradigm, compared to placebo. There was also a significant medication × stress × trial interaction indicating that varenicline attenuated cue induced craving following neutral imagery but not when cues were preceded by stress induction (i.e., stress + cues). Conclusions: These results elucidate the biobehavioral effects of varenicline for nicotine dependence and suggest that varenicline-induced amelioration of cigarette craving is unique to tonic craving and cue- induced craving following neutral imagery but does not extend to the combination of stress plus cues. © 2013 Published by Elsevier Ireland Ltd. 1. Introduction Stress has been implicated as a central mechanism to drug relapse (Uhart and Wand, 2009), including cigarette smoking, with prospective research demonstrating that psychological stress and negative affect predict smoking lapses (Shiffman and Waters, 2004). In a recent study, 62% of smokers attributed their inabil- ity to stop smoking to stress (Hughes, 2009). Likewise, research has shown that cue-reactivity is a predictor of smoking behavior and relapse (Niaura et al., 1989; West, 2009), although recently this association has been called into question (Perkins, 2012). Preclinical studies provide compelling evidence of the ability of cue- and stress-exposure to reinstate nicotine-seeking behavior. For example, reintroduction to visual stimuli that had previously been paired with nicotine reinstated nicotine-seeking behavior in ∗ Corresponding author at: University of California, Los Angeles, Psychology Department, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095-1563, United States. Tel.: +1 310 794 5383; fax: +1 310 206 5895. E-mail address: lararay@psych.ucla.edu (L.A. Ray). rats (Liu et al., 2006) and presentation of nicotine-associated cues following extinction produces reinstatement, above and beyond nicotine priming (LeSage et al., 2004). Likewise, preclinical mod- els of stress exposure (e.g., foot shock paradigm) have supported stress-induced nicotine reinstatement (Buczek et al., 1999), which in turn represents a pharmacological treatment target (Yamada and Bruijnzeel, 2011; Zislis et al., 2007). Together, the preclin- ical data suggest that both cigarette cues and stress play a critical role in nicotine reinstatement and nicotine-seeking behav- iors. While preclinical studies have effectively dissociated mech- anisms of stress- and cue-induced reinstatement, psychological models of craving argue that stress serves as an internal or affec- tive cue, which in turn triggers craving in a similar fashion to smoking cues (Baker et al., 2004). Early experimental studies docu- mented increases in smoking during conditions of stress (Schachter et al., 1977) and anxiety (Pomerleau and Pomerleau, 1987). In addi- tion, several recent studies found that psychosocial stress, induced using the Trier Social Stress Test, reliably increases cigarette craving (Buchmann et al., 2010; Childs and de Wit, 2010) and that smok- ers have overall lower hormonal stress responsivity (al’Absi et al., 0376-8716/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.drugalcdep.2012.12.015